| Background:Endoscopic submucosal dissection(ESD)is commonly performed for gastric mucosal lesions such as early gastric cancers(EGC)and adenomas.Post-ESD bleeding is one of the important complications.The reported rate of post-ESD bleeding ranged from 0.6% to 26.9%.The majority of bleeding occurs within 24 hours after the procedure.PPIs have been recommended by many guidelines and consensus statements to reduce post-ESD bleeding.However there is no optimal regimen of PPI for patient undergoing ESD.Currently,the clinical practice to treat post-ESD bleeding is mainly based on the strategy for peptic ulcer,High dose continuous PPIs(80 mg intravenous bolus dose of a PPI followed by a continuous infusion at 8 mg/h for 72 hours)has become the standard practice in the management of peptic ulcer bleeding.The pathophysiology of peptic uclers and ESD-induced ulcers are very different.First,peptic ulcer is considered an acid related condition.ESD is used to treat early gastric cancers.There is often associated mucosal atrophy and the stomach is achlorhydric.Second,peptic ulcers can erode through the full thickness of the stomach wall and into serosal arteries.ESD induced ulcers are often shallow and bleeding from these ulcers originate from vessels confined to the submucosal layer.Third,exposed visible vessels at the base of artificial ulcers are all treated with prophylactic hemostasis during the ESD operation while only the peptic ulcers with high risk endoscopic findings(Forrest Ia-IIb)receive endoscopic hemostasis.Artificial ulcer is relatively easy to heal,and the risk of post-ESD bleeding is low.Proton pump inhibitors(PPIs)are commonly prescribed after ESD procedures.The optimal dose remains undefined.In patients with bleeding peptic ulcers,a meta-analysis including 13 randomized clinical trials suggested that intermittent low dose PPI therapy was comparable to continuous high dose PPI in the prevention of further bleeding after endoscopic hemostasis.However,there are few reports on the comparative efficacy of intermittent low dose and continuous high dose PPIs in patients undergoing ESD.Only two randomized controlled trials from Korea compared intermittent and continuous pantoprazole for the prevention of bleeding after ESD.These two trials were both single-center studies,and pantoprazole was given before the ESD procedure.Neither trial defined the follow-up time of post-ESD bleeding.Second look endoscopy was performed one day after ESD.Both studies did not find difference in both the rates of intra-procedural and post-ESD bleeding.Due to the study design of previous trials,the role of low dose PPI in post-ESD need to be further clarified.Objective:In this study,we hypothesized that the use of low-dose intermittent esomeprazole would not be inferior to a high-dose continuous regime in the prevention of bleeding after ESD for early gastric cancer and precancerous mucosal lesions.Methods:This multicenter,non-inferiority,randomized controlled trial was conducted at 9hospitals in China.Consecutive eligible patients(≥18 years)with a diagnosis of gastric mucosal lesions after ESD treatment were randomly assigned(1:1)to receive either intermittent(esomeprazole 40 mg intravenously twice a day for 3 days.)or continuous(esomeprazole 80 mg bolus injection followed by a continuous infusion at 8 mg/h for 3 days)PPIs treatment.After three days,all patients administered orally esomeprazole 40 mg once a day for 8 weeks.Randomisation was done by an independent statistician using a computer-generated random number,and kept in sealed,opaque envelopes.Endoscopists were blinded to treatment allocation.The primary endpoint was post-ESD bleeding within 7days.Analysis was done according to the intention-to-treat principle with the non-inferiority margin(Δ)of 5% 。 This study was registered with Clinical Trials.gov,number Chi CTR-IOR-17012738.ResultsParticipants and baseline characteristicsWe screened 526 consecutive patients who were diagnosed with gastric mucosal lesions from 30 September 2017 to 30 July 2019,and 487 patients were suitable for ESD treatment.Seventy-three patients were excluded because of severe comorbidity(n=16),taking anticoagulants(n=25),recurrent lesions(n=8),and refusing ESD treatment(n=24).A total of414 patients were randomized,209 patients were assigned to Group A(low-dose PPI group)and 205 to Group B(high-dose PPI group).Post-ESD bleedingThe total 7-day post-ESD bleeding occurred in 14 of 209(6.7%,95% CI 3.3%-10.5%)in the low-dose group,and 12 of 205(5.9%,95% CI 2.9%-9.3%)in the high-dose group(P=0.723).The absolute risk reduction(AAR)and 95% CI was 0.84%(-3.83,5.5).In the low-dose group,8 of the 14(57.14%)patients underwent endoscopic hemostasis.Five patients presented with hematemesis within 24 hours after ESD,two patients presented with melena,and one patient was confirmed bleeding on second look endoscopy in seventh day after ESD.One patient received surgical hemostasis after endoscopic treatment failed.Only one patient was admitted to the intensive care unit for two days due to post-ESD bleeding.Only one patient received two units of blood transfusion.In high-dose group,6 of the 12(50%)patients underwent endoscopic hemostasis.Two patients presented with hematemesis within 24 hours after ESD,one patient presented with melena,and three patients were confirmed bleeding on second look endoscopy in seventh day after ESD.One patient was admitted to the intensive care unit for two days due to post-ESD bleeding.Only one patient received four units of blood transfusion.A total of 14 patients in the low dose group developed recurrent bleeding within 7 days after ESD,while 12 patients suffered bleeding in the high dose group.Bleeding incidence risks at 1,3 and 7 days were estimated by Kaplan-Meier analysis and compared between treatment groups using the log-rank test(P>0.05)(Figure 3).During the two-month follow-up,there was no bleeding after 7 days.There was no death in two groups.Other outcomesAmong the 414 patients,gastroscopy was completed in 212(51.20%,212/414)in the first month after ESD.A total of 110(52.63%)of 209 patients in the low-dose group and 102(49.76%)of 205 patients in the high-dose group had completed gastroscopy in the first month after ESD.In ITT analysis,patients who did not undergo gastroscopy were classified as active stage,the result showed that 121(57.9%,121/209)ulcers were in the activity stage,44(21.2%,44/209)ulcers were in the healing stage and 44(21.2%,44/209)ulcers were in the scar stage respectively in low-dose group.In high-dose group,122(59.5%,122/205)ulcers were in the active stage,44(21.5%,44/205)ulcers in the healing stage,and 39(19%,39/205)ulcers were in the scar stage,respectively.There was no difference in the distribution of healing stages between the two groups(P=0.875).Five patients in each group underwent additional curative surgery because post-ESD histopathological diagnosis of invasive gastric cancer.Four patients in the high-dose group and six patients in the low-dose group with non-curative resection refused further surgical treatment.All 414 patients were followed for two months after ESD;no related ESD perforation or infection occurred in either group.The hospital stay was 10.0(8.0-12.0)days in the low-dose PPI group,which was similar to high-dose group(P=0.973).There was no statistically significant difference in hospital costs between the two groups(P=0.816).Conclusion:The use of low-dose esomeprazole is not inferior to high-dose esomeprazole in the prevention of post-ESD bleeding.Trial registration number: Chi CTR-IOR-17012738.Background:Extranodal NK/T-cell lymphoma,nasal type(ENKTL-NT)is a rare type of non-Hodgkin’s lymphoma(NHL).It is rare in North American and European countries,but it is prevalent in Asia and South America and presents increasing incidence in the U.S.ENKTL-NT presents an aggressive clinical course and a poor prognosis,especially for advanced disease.Most ENKTL cases occur in the nasopharyngeal area,but other affected sites include the gastrointestinal tract,lung,skin,testis,and muscles.Intestinal NK/T cell lymphoma is rare.There are some distinctive ethnic and geographic differences.Little is known regarding the clinical characteristics of intestinal NK/T cell lymphoma,which may be one of the main reasons for the delay in diagnosis and appropriate treatment.To our knowledge,there has been no large sample epidemiological study on intestinal NK/T cell lymphoma.Therefore,we retrospectively analyzed the clinicopathological features and endoscopic findings of 13 primary intestinal NK/T cell lymphomas at our center and reviewed the current literature to improve our understanding of this disease.Aims:To provide clinicopathological features and endoscopic findings and to summarize the treatment outcomes of intestinal NK/T cell lymphoma to improve our understanding of this disease.Methods:This study is divided into two parts.In the first part;we retrospectively analyzed the clinical,endoscopic and pathological characteristics of 13 patients diagnosed with intestinal NK/T cell lymphoma between January 2011 to December 2016 in Xinqiao hospital of Army Military Medical University.In the second part,we systematically evaluated the literature of intestinal NK/T cell lymphoma.Results:PartⅠ Single center case series:A total of 27 cases of intestinal T cell and NK cell lymphoma were confirmed in the Xinqiao Hospital of Army Military Medical University from January 2011 to December 2016,among which 13 cases(13/27,48%)diagnosed gastrointestinal NK/T cell lymphoma included in this study.The median diagnosed age of the included patients was 39 years(15-71 years),9 patients(9/13,69.2%)were male and 4 patients(4/13,30.8%)were female.The median time from symptom to diagnosis was 3.8 months(2-9 months).The common clinical manifestations included abdominal pain(10/13,76.9%),gastrointestinal bleeding(6/13,46.2%)and diarrhea(3/13,23.1%).At the time of diagnosis,6 patients(6/13,46.2%)had symptoms B(fever,night sweats,and weight loss)and 4 patients(4/13,30.8%)had elevated lactate dehydrogenase.According to Mussoff gastrointestinal non-hodgkin’s lymphoma staging system for clinical stage,phaseⅠ,76.92%(10/13),10 patients,phaseⅡ,2 patients(2/13,15.38%),and one patient(1/13,7.69%)with stage Ⅲ.Among the 13 patients,3 patients were confirmed by a single gastroscopy,with an average of 5.3 pieces of tissue for each patient,three patients were confirmed by two times of endoscopy and biopsy,and 7.7 pieces of tissue for each patient on average.Seven patients were finally confirmed by surgical specimens,and each patient received 1-3 times of endoscopic examination before surgery.All 13 patients had multiple lesions,9 lesions were in the large intestine(including ileocecal,colonic,and rectum),3 lesions were in the small intestine,and 1 lesion was in the duodenum.All the 13 patients presented with multiple ulcers under endoscopy,with a diameter about 1.5cm-6cm.Nine patients(9/13,69.2%)manifested ulcerative lesions and 4 patients(4/13,30.8%)presented ulceroinfiltrative lesions.Histopathology,necrosis was observed in all 13 specimens and ulceration was observed in 12.There were 9 cases of lesions in the large intestine(including ileocecal,colonic and rectal),3 cases in the small intestine,and 1 case in the duodenum.Invasion to the serous layer was observed in 5 of the 7 surgical specimens,epidermotropism was observed in 1 specimen,and crypt atrophy was observed in 3 specimens.The tumor cells were predominantly medium to small in size(7/13,53.8%).Eleven cases(11/13,84.6%)showed pleomorphic tumor cells with an irregular nucleus.Angiocentricity was found in 11 cases.Neurotropism and gangliocyte hyperplasia were seen in 3 and 2 cases.Immunohistochemical results of tumor tissues in these cases showed positive CD3,CD43,TIA-1 and granulase B,and negative CD20 and CD5.CD56 was expressed in 10(10/13,81.3%)specimens.The Ki-67 index of 13 specimens was 30%-70%.All specimens can be found diffused EBER positive.T cell gene rearrangement was performed in 12 patients,all of which were poly clonal.Seven patients received emergency surgical treatment.Six patients received emergency surgical treatment due to bowel perforation and 1 patient received emergency surgical treatment due to gastrointestinal massive hemorrhage.Among the patients undergoing surgery,4 patients died of complications one week after surgery,one patient received postoperative chemotherapy,and two patients were unwilling to receive postoperative chemotherapy.Six patients received only systemic chemotherapy.Chemotherapy regimens included CHOP(cyclophosphamide,vincristine,doxorubicin,and prednisone),CTOD(cyclophosphamide,pirarubicin,vincristine and dexamethasone),COTP(cyclophosphamide,vincristine,pirarubicin,prednisone),TAOD+L-ASP(cytarabine,pirarubicin,vindesine,dexamethasone and pegaspargase),and CVTLD(cyclophosphamide,vincristine,pirarubicin,dexamethasone and pegaspargase).By the time of follow-up,10 of the 13 patients(10/13,77%)have died of intestinal NK/T cell lymphomas,and the other 3 surviving patients were diagnosed within the last 9 months.The longest survival time was 13 months;the median survival time was 6 months.Five patients died within one week after the diagnosis of NK/T cell lymphoma.Four of them received emergency surgery: 3 patients due to bowel perforation,and one patient who underwent surgery in other hospital due to bowel perforation one month prior who experienced gastrointestinal bleeding postoperative and was transferred to our hospital for emergency treatment.Survival curves were plotted for gender,age,the location of the lesion,whether they received emergency surgery and whether they received chemotherapy.As shown in Figure S1,gender,age,the location of the lesion,whether they received emergency surgery and whether they received chemotherapy did not significantly affect overall survival(p> 0.05).Part II systematic review306 articles were retrieved from the Chinese and English database,and 2 additional articles were consulted.A total of 308 articles were initially retrieved,and a total of 166 articles were obtained after the exclusion of duplicate articles.By reading literature titles and abstracts,145 irrelevant studies were excluded.A total of 21 studies were included for full-text screening,excluding 6 case reports,3 reviews,and 2 studies with a sample size less than 10 patients.Finally,a total of 10 studies including 292 patients that were included.Two of studies are from South Korea,and the other eight are from China.All the 10 studies were retrospective studies.One study is a multi-center study,and the other 9 are single-center studies.There were clear diagnostic criteria in all 10 studies.One article did not describe the endoscopic characteristics of lesions.Survival and follow-up were not described in detail in one article.The median diagnosed age of onset of intestinal NK/T cell lymphoma was 33-45 years,the minimum age was 7 years,and the maximum age was 79 years.A total of 292 patients were included,including 202 males and 90 females.The ratio of male to female is 2.24:1.The most common clinical manifestations were abdominal pain,fever,gastrointestinal bleeding and perforation.Two cases located in the esophagus,10 cases in the stomach,108 cases in the small intestine(including the duodenum),33 cases in the ileocecal region,109 cases in the colorectal region,and 60 cases had multiple lesions.There were 119 patients with specific morphology under endoscopy,including 111 patients with ulcer and 8 patients with mass.A total of 191 patients(191/292,65.4%)with intestinal NK/T cell lymphoma received surgical treatment,most of them underwent emergency surgical treatment for bowel perforation or massive gastrointestinal hemorrhage during the course of the disease.20.9%(61/292)of the patients received surgery alone,44.5%(130/292)of the patients received surgery combined with postoperative chemotherapy,23.3%(68/292)of the patients received chemotherapy alone,and 10.3%(30/292)of the patients received no treatment.The median survival time of patients was from 2 to 12.7 months,the shortest survival time was 1 day and the longest survival time was 66 months.Conclusion:Intestinal NK/T cell lymphoma shows nonspecific clinical features and poor prognosis,which is mainly expressed as ulcers on endoscopy.Emergency surgery may be an adverse prognostic factor of lymphoma,since it is prone to progress toward gastrointestinal perforation. |
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